Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol
Authors: Gerhardt Attard, Laura Murphy, Noel W Clarke, Ashwin Sachdeva, Craig Jones, Alex Hoyle, William Cross, Robert J Jones, Christopher C Parker, Silke Gillessen, Adrian Cook, Chris Brawley, Clare Gilson, Hannah Rush, Hoda Abdel-Aty, Claire L Amos, Claire Murphy, Simon Chowdhury, Zafar Malik, J Martin Russell, Nazia Parkar, Cheryl Pugh, Carlos Diaz-Montana, Carmel Pezaro, Warren Grant, Helen Saxby, Ian Pedley, Joe M O'Sullivan, Alison Birtle, Joanna Gale, Narayanan Srihari, Carys Thomas, Jacob Tanguay, John Wagstaff, Prantik Das, Emma Gray, Mymoona Alzouebi, Omi Parikh, Angus Robinson, Amir H Montazeri, James Wylie, Anjali Zarkar, Richard Cathomas, Michael D Brown, Yatin Jain, David P Dearnaley, Malcolm D Mason, Duncan Gilbert, Ruth E Langley, Robin Millman, David Matheson, Matthew R Sydes, Louise C Brown, Mahesh K B Parmar, Nicholas D James, Elin Jones, Katherine Hyde, Hilary Glen, Sarah Needleman, Ursula McGovern, Denise Sheehan, Sangeeta Paisey, Richard Shaffer, Mark Beresford, Zafar Malik, Anjali Zarkar, Emilio Porfiri, David Fackrell, Ling Lee, Thiagarajan Sreenivasan, Sue Brock, Simon Brown, Amit Bahl, Mike Smith-Howell, Cathryn Woodward, Mau-Don Phan, Danish Mazhar, Krishna Narahari, Jacob Tanguay, Fiona Douglas, Anil Kumar, Abdel Hamid, Azman Ibrahim, Dakshinamoorthy Muthukumar, Matthew Simms, Jane Worlding, Anna Tran, Mohammed Kagzi, Prantik Das, Carmel Pezaro, Virgil Sivoglo, Benjamin Masters, Pek Keng-Koh, Caroline Manetta, Duncan McLaren, Nishi Gupta, Denise Sheehan, Stergios Boussios, Henry Taylor, John Graham, Carla Perna, Lucinda Melcher, Warren Grant, Katherine Hyde, Ami Sabharwal, Uschi Hofmann, Robert Dealey, Neil McPhail, Robert Brierly, Simon Brown, Lisa Capaldi, Norma Sidek, Peter Whelan, Thiagarajan Sreenivasan, Peter Robson, Alison Falconer, Sarah Rudman, Sindu Vivekanandan, Vinod Mullessey, Sarah Needleman, Maria Vilarino-Varela, Vincent Khoo, Karen Tipples, Mehran Afshar, Alison Falconer, Patryk Brulinski, Vijay Sangar, Clive Peedell, Ashraf Azzabi, Peter Hoskin, Viwod Mullassery, Santhanam Sundar, Yakhub Khan, Ruth Conroy, Andrew Protheroe, Judith Carser, Paul Rogers, Lisa Capaldi, Kathryn Tarver, Stephanie Gibbs, Mohammad Muneeb Khan, Mohan Hingorani, Ashraf Azzabi, Simon Crabb, Manal Alameddine, Neeraj Bhalla, Caroline Manetta, Robert Hughes, John Logue, Darren Leaning, Salil Vengalil, Ashraf Azzabi, Daniel Ford, Georgina Walker, Ahmed Shaheen, Omar Khan, Andrew Chan, Imtiaz Ahmed, Serena Hilman, Fiona Douglas, Anil Kumar, Anna Tran, Sangeeta Paisey, Ian Sayers, Lisa Capaldi, Ashok Nikapota, David Bloomfield, Tim Porter, Joji Joseph, Cyrill Rentsch, Ricardo Pereira Mestre, Enrico Roggero, Jörg Beyer, Markus Borner, Raeto Strebel, Dominik Berthold, Daniel Engeler, Hubert John, Razvan Popescu, Donat Durr
Journal: The Lancet Oncology (2023)

BackgroundAbiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival.MethodsWe analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544).FindingsBetween Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial).InterpretationEnzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years.FundingCancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.